The Economic Impact of Acute Exacerbations of Chronic Bronchitis in the United States and Canada: A Literature Review

BACKGROUND: Acute exacerbations of chronic bronchitis (AECB) are recurrent and potentially severe medical events for the 13 million people in the United States who have chronic bronchitis. Medical resource use associated with AECB can have a substantial economic impact on the patients, health care system, and society overall. OBJECTIVES: To evaluate literature on the economic impact of AECB in terms of cost of illness, cost of treatments, and cost-effectiveness. METHODS: A MEDLINE literature search was conducted for studies of chronic bronchitis and costs. Reference lists of identified articles were also retrieved for review. RESULTS: Eight published studies were identified: 2 cost-of-illness studies, 1 comparative cost study, and 5 cost-effectiveness studies. Important drivers of costs associated with AECB include hospitalization and choice of antibiotics. In mild to moderate AECB, patient adherence with therapy is essential to consider when selecting treatment. The antibiotic with the lowest acquisition cost has not been shown to be the most cost effective, as adherence and clinical outcomes, particularly re-hospitalization rates, differ. CONCLUSIONS: Further research in these areas is needed to guide clinical decision making and the conduct of disease management programs.

cute exacerbations of chronic bronchitis (AECB), as the name suggests, is acute inflammation of the bronchial airways in the presence of underlying chronic bronchitis. 1 AECB is generally accompanied by bacterial infections for which standard treatment is antibiotics. 2 Approximately 13 million persons in the United States (almost 5% of the adult population) have chronic bronchitis and experience acute exacerbations. 3,4 As such, in addition to its clinical effects, AECB is likely to have a substantial economic impact.
A variety of studies have been performed to assess the costs associated with AECB and its treatment. These studies can be grouped into 3 main categories: cost-of-illness studies, which evaluate the baseline resource utilization and costs associated with AECB; comparative cost studies, which assess the difference in costs resulting from different AECB treatments; and cost-effectiveness studies, which determine the incremental change in cost per incremental improvement in patient outcomes for different AECB treatments. Each of these types of studies provides unique information on the impact of AECB. Cost-of-illness studies, also known as burden-of-illness studies, provide an assessment of all costs associated with a condition and may include societal as well as direct and indirect medical costs. Comparative cost studies are important in the evaluation of the relative costs of treatments and may be important to treatment selection. Cost-effectiveness studies, by providing a common metric such as cost per quality-adjusted lifeyear (QALY) or symptom-free day, allow for comparisons across conditions and are most appropriate for societal or health plan allocation decision making.

■■ Methods
To better understand the economic impact of AECB, we reviewed the economic literature for this condition. A MEDLINE literature search was conducted to identify articles with the MeSH headings "Pulmonary Disease, Chronic Obstructive," "Pulmonary Emphysema," or "Bronchitis, Chronic" and headings involving the term "Cost." There was no time or language limitation to the search, and we did not limit the search to articles with abstracts available online. Only articles providing information on medical care costs for AECB in the United States or Canada were selected. Reference lists of identified articles were reviewed for additional relevant information.

■■ Literature Search Results
A total of 8 published studies on the medical care costs of AECB in the United States and Canada were identified. Two of these are cost-of-illness studies, in that they provide information only on the medical care costs (either inpatient only or inpatient plus outpatient) for the broad population of AECB patients. One of the identified studies is a comparative cost study, presenting differences in medical care costs for AECB patients treated with differing antibiotic therapies. Finally, 5 of the studies are cost-effectiveness studies, in that they compared both the costs and clinical outcomes for patients treated with a number of specified antibiotics. (See Table 1 for a summary of reviewed studies.)

Cost-of-Illness Studies
We identified 2 studies that assessed total costs associated with AECB in the United States and Canada. Both studies included data on inpatient treatment; one also included estimates of costs associated with outpatient care for AECB.
Niederman et al. conducted a retrospective analysis using claims and survey data to assess resource utilization and health care system costs for patients treated for AECB. 5 Medicare The Economic Impact of Acute Exacerbations of Chronic Bronchitis in the United States and Canada: A Literature Review Summary of Reviewed Studies*

Comparative Cost Study
Destache et al. 7 United States Retrospective Patient data obtained from medical records between January 1990 and January n=60 patients with 1994. Patients were older than 36 years with mild-to-moderate acute infections 373 AECB and diagnosed chronic bronchitis documented in records. Three antibiotic groups Data collected 1/1990-1/1994 were selected for comparison and were categorized as first-, second-, and third-($U.S.1994) line agents.

Cost-effectiveness Studies
Grossman et al. 8 Canada Randomized, multicenter, Outpatient adult men and women aged 18 years or older with chronic bronchitis parallel-group, open-label and a recent history of frequent exacerbations (3 or more within the past year) study; n=240 (120 were randomized to receive either oral ciprofloxacin (500 mg bid) or usual care. ciprofloxacin, 120 usual care) Patients were seen at months 3, 6, 9, and 12 for regular visits. Patients Data collected 11/1993-completed 3 self-administered questionnaires at regular and follow-up visits. 11/1995 ($Canadian1999) Halpern et al. 9 United States Retrospective analysis of data Analysis of clinical trial data from 386 patients treated at 46 centers in the and Canada from a randomized, United States and 52 patients at 10 centers in Canada. Treatment effectiveness prospective study measured as the proportion of patients without recurrence requiring n=438 (215 gemifloxacin, antibiotic treatment following resolution of the initial AECB. 224 clarithromycin) Data collected 11/1998-11/1999 ($U.S.1999) Keenan et al. 11 Canada Retrospective analysis of data Analysis of data from published meta-analyses. Decision-analysis model from published meta-analyses developed. Primary outcomes included reductions of in-hospital mortality Reports published 1993-1998 and endotracheal intubations among patients treated with noninvasive ($Canadian1996) positive pressure ventilation plus usual care versus usual care alone.
Quenzer et al. 12 United States Retrospective analysis of data Analysis of 12 trials of clarithromycin, 6 of which included patients with collected from 12 randomized, AECB. (Others included pneumonia, AECB and pneumonia, or sinusitis.) double-blind controlled trials The analysis estimated additional cost per complication-free cure, meaning conducted 1987-1992 a full course of therapy, satisfactory response, and no adverse events. ($U.S.1995) Smith and Pesce 10 United States Retrospective analysis of data Clinical and utility data were derived from published accounts. Cost data from published reports were from Medicare reimbursement rates. The model compared cost/QALY (published 1972-1989) for treatment of AECB with PAC versus no PAC, given assumptions about ($Canadian1992) life expectancy following hospitalization.

Cost-of-Illness Studies
Niederman et al. 5 United  claims data from 1994 were used to estimate inpatient and outpatient utilization rates and costs for patients aged >65 years. For patients <65 years, estimates were generated from the National Healthcare and Cost Utilization Project, the National Ambulatory Medical Care Survey, and the National Hospital Ambulatory Medical Care Survey. Inpatient resource utilization and charges for the <65 years group were inflated from 1994 to 1995 dollars (to have consistent inpatient and outpatient costs), while outpatient resource utilization rates and charge data were taken from the average of survey data from 1993 through 1995; 1995 costs were applied to both the inpatient and outpatient resource utilization rates.
In their analysis, Niederman and colleagues reported that the total direct treatment costs of AECB were largely attributable to costs of hospitalizations. 5 The total annual AECB treatment costs for patients >65 years were $1.2 billion, while the cost for patients <65 years were $419 million. Total inpatient hospital costs for the >65 years group were $1.1 billion (92% of total costs) and $408 million (97% of total costs) for the <65 years group. The average hospital charges incurred, in 1995 dollars, were equal to $5,497 per patient aged >65 years and $5,561 per patient <65 years. Inpatient physician services account for an additional $32 million and $11 million for the >65 years and <65 years groups, respectively. Outpatient services data, although less reliable than inpatient data because diagnosis codes are often used interchangeably across respiratory diseases in outpatient data, indicated $24.9 million for the >65 years group and $15.1 million for those <65 years.
Based on 1998-1999 data from the University HealthSystem  6 Results were similar between the 2 data sources and comparable to the values reported by Niederman et al. 5 The average cost of inpatient hospitalization for AECB was $6,285 for UMHS and $6,625 for UHC. Inpatient hospitalization costs for all acute and chronic bronchitis were $6,287 for UMHS and $6,524 for UHC.

Comparative Cost Studies
Destache et al. used retrospective data to evaluate the efficacy and cost-effectiveness of antimicrobial therapy for patients with AECB. 7 Data were obtained from medical records in the Pulmonary Department of Creighton University School of Medicine between January 1990 and January 1994. Patients with mild-to-moderate acute infections and a documented diagnosis of chronic bronchitis were eligible for the study. A total of 60 patients with 224 documented episodes of AECB were included in the analysis. Prior to data collection and review, a group of resident pulmonologists was asked to categorize the antibiotics prescribed for each documented episode of AECB into one of 3 groups. The antibiotics were categorized as first-line agents (amoxicillin, tetracyclines, erythromycin), second-line agents (cephradine, cefuroxime, cefaclor, cefprozil), and third-line agents (amoxicillin/clavulanate, azithromycin, ciprofloxacin). However, the AECB data analysis did not distinguish between antibiotics used for the initial presentation of  AECB and those used for subsequent presentations. The costs associated with treatment for the initial and subsequent AECB episodes and the time between episodes were used to evaluate the efficacy and cost-effectiveness of each antibiotic treatment group. The total charges for treating AECB were determined by summing charges for laboratory work, office visits, radiology, antibiotics, and hospitalizations. The average total charges for treatment of AECB in each group, expressed in 1994 U.S. dollars, were $942 ± $2,173 for patients treated with firstline agents, $563 ± $2,296 for second-line agents, and $542 ± $1,946 for third-line agents (P<0.05, first-versus third-line). The average pharmacy costs associated with AECB were lowest for first-line agents; however, costs for other components of resource utilization for first-line therapy patients more than offset these savings. Treatment failure in patients receiving first-line agents occurred significantly more frequently than in those receiving third-line agents (19% versus 7%, P<0.05).
A significant difference was also observed in the hospitalization rate for AECB within 2 weeks of outpatient treatment for patients prescribed first-line agents compared to those prescribed third-line agents (18.0% versus 5.3%, respectively). In addition, the mean time between subsequent AECB episodes requiring treatment was significantly different among the 3 treatment groups: first-line agents, 17.1 ± 22.0 weeks; second-line agents, 22.7 ± 30.0 weeks; and third-line agents, 34.3 ± 35.5 weeks (P<0.005). The authors concluded that compared to first-or second-line agents, the use of third-line antimicrobial agents reduced the treatment failure rate, need for hospitalization, and overall costs of care as well as prolonged the time between AECB episodes.

Cost-effectiveness Studies
Five studies were identified as reporting on cost-effectiveness of treatments for AECB: 3 presented incremental cost-effectiveness, 2 reported on antibiotic treatments, 8,9 and 1 reported on pulmonary artery catheterization. 10 Two other studies presented costs and outcomes related to noninvasive positive pressure ventilation 11 and cost per complication-free cure 12 but did not present incremental cost-effectiveness ratios between treatments. Hospitalization and costs associated with treatment failure were the single largest cost driver in each of the studies, while drug costs were generally responsible for a smaller proportion of the total treatment costs.
Quenzer et al. developed a computerized pharmacoeconomic model to evaluate the impact of clinical response and adverse drug events on cost and cost-effectiveness of clarithromycin compared with those of 7 alternative antibiotics (amoxicillin/clavulanate, ampicillin, cefaclor, cefixime, cefuroxime, clarithromycin, erythromycin) used to treat lower respiratory tract infections (LRTI). 12 Cost data were obtained from 12 randomized, controlled, clinical trials conducted between 1987 and 1992 in outpatient clinics in the United States. A total of 2,377 patients, treated for acute exacerbations of chronic bron-chitis (n=1,102), pneumonia (n=591), or a combination of the 2 conditions (n=201) were enrolled in the clinical trials from which data were used in the cost-effectiveness study.
The mean total costs per episode ranged from $137 to $267, depending on the starting medication. Drug acquisition costs accounted for a small percentage of the total treatment cost (4.3% to 32.4%) compared to clinical costs (including costs of treatment failure), which represented the largest percentage (45.9% to 62.2%) of the overall costs. The "cost-effectiveness analysis" was based on the proportion of patients with a complication-free cure (CFC), defined as a full course of therapy with a successful response and no adverse drug events (ADEs). It is important to note that this is not a true cost-effectiveness value, as it provides the overall cost per outcome for a single therapy rather than the incremental cost per incremental outcome as compared to another therapy. The mean cost per CFC ranged from $307 for clarithromycin to $612 for cefaclor. The ranked order of the 7 antibiotics from lowest to highest cost per CFC was: clarithromycin, cefixime, amoxicillin/clavulanate, erythromycin, cefuroxime, ampicillin, and cefaclor. Incremental cost per CFC ratios of all agents compared to the least expensive demonstrated additional costs per CFC that ranged from $145 for clarithromycin to $899 for cefuroxime. This study concludes that the costs associated with treatment failure and ADEs contribute substantially to the overall cost and "cost-effectiveness" of antibiotics used in the treatment of LRTI in the outpatient setting.
The Canadian Ciprofloxacin Health Economic Study Group conducted a prospective, randomized, open-label study to compare the annual "costs, consequences, effectiveness, and safety of ciprofloxacin versus standard antibiotic care," for patients with AECB. 8 The study population consisted of 240 patients (120 in each group), aged 18 years and older, with a history of 3 or more exacerbations within the past year. Patients were randomized to receive either oral ciprofloxacin (500 mg bid) or usual care, defined as "any antibiotic or combination of antibiotics other than a quinolone antibiotic (except under special circumstances)." Patient assessments occurred at 3-, 6-, 9-, and 12-month intervals. Annual cost estimates included antibiotics prescribed for AECB, concomitant medications, hospitalizations, emergency department visits, outpatient resources such as diagnostic tests and procedures, time lost from work, and patient and caregiver out-of-pocket expenses.
Patients in the ciprofloxacin treatment group had lower costs for concomitant medications, time lost from work, and out-of-pocket expenses for patients and caregivers. Cost of antibiotics accounted for less than 6% of the total annual cost per patient in each treatment group. Hospitalizations represented 42% ($1,329 ± $6,064 [SD], Canadian $) of the total annual cost in the ciprofloxacin group compared to 18% ($459 ± $2,169 [SD]) in the usual care group. The only statistically significant predictors of hospitalizations were duration (P=0.004) and severity (P=0.004) of chronic bronchitis. The overall mean annual cost of AECB in the ciprofloxacin group was $3,194 ± $6,575 (SD) and $2,617 ± $3,300 (SD) in the usual care group. Cost-effectiveness analysis of ciprofloxacin as compared to usual care demonstrated an incremental cost of $209 per additional AECB symptom day avoided. The incremental cost per QALY gained for ciprofloxacin compared to usual care was $18,588. This value is below even the most conservative thresholds for assessment of cost-effectiveness, suggesting that the incremental cost associated with use of ciprofloxacin is justified by its benefits.
Halpern et al. conducted an economic analysis based on data from the Gemifloxacin Long-Term Outcomes in Bronchitis Exacerbations (GLOBE) study. 9 This prospective double-blind, controlled, health outcomes study compared health economic and clinical outcomes after randomized treatment with either oral gemifloxacin or oral clarithromycin for AECB. This study included 386 patients at 46 centers in the United States and 52 patients at 10 centers in Canada. Treatment effectiveness was measured as the proportion of patients without recurrence requiring antibiotic treatment following resolution of the initial AECB.
Compared with clarithromycin, gemifloxacin treatment resulted in significantly more patients without AECB recurrence requiring antibiotic treatment after 26 weeks (73.8% s.]). The mean direct cost per patient receiving gemifloxacin was $127 less than the comparable cost with clarithromycin ($247 versus $374, respectively, n.s.); mean per-patient total costs (direct plus indirect) were $329 less for patients receiving gemifloxacin ($1,413 versus $1,742, n.s.). Among direct costs, hospitalizations were the largest component, corresponding to 46% of total gemifloxacin costs and 60% of clarithromycin costs. Gemifloxacin dominated clarithromycin in cost-effectiveness analysis; that is, gemifloxacin treatment resulted in both improved outcomes and decreased costs (either direct or direct plus indirect) as compared to clarithromycin treatment.
The cost-effectiveness of 2 treatments associated with severe AECB has been reported. In the first, a meta-analysis of randomized, controlled trials was used to determine effectiveness parameters for a decision-analytic model comparing noninvasive positive pressure ventilation (NPPV) plus standard therapy versus standard therapy alone for severe AECB. 11 Published literature and regional databases of health care resource utilization were used to provide costs for each node of the model. Clinical variables included probability of requiring early or late intubation, slow versus short wean, acquiring ventilator-associated pneumonia, length of intensive care unit and regular ward hospital stay, and probability of dying associated with various therapies. In the base case, the average cost for patients treated with NPPV was estimated to be $7,211 (1996 Canadian $) versus $10,455 for standard therapy only, and NPPV was superior on both outcome measures (decreased need for endotracheal intubation by 37.5% and hospital mortality by 16.1%), suggesting that adjunct NPPV dominated standard therapy alone. Sensitivity analyses demonstrated lower costs for standard therapy alone only when the rate of intubation was greater for NPPV than for standard therapy.
Smith and Pesce (1994) evaluated cost-effectiveness of pulmonary artery catheterization (PAC) among patients with severe AECB requiring mechanical ventilation. 10 Costs were obtained from Medicare reimbursement rates, and clinical probabilities were derived from published data. Utility values were estimated; the model assumed posthospital survival of 1.74 years. Sensitivity analyses were performed around all variables. The incremental cost per QALY associated with the use of PAC compared to standard care was $77,407 (1992, U.S.$). If survival were improved by 8.7% (base case estimate is 5%), the cost/QALY would decrease to $50,000, a value considered to be the upper threshold for acceptable cost-effectiveness in the literature. 13

■■ Limitations
While most of the studies included in this review were recently published, a number of the studies contain data that are several years old. Further, the studies reviewed here were not consistent in their costing methodology, and not all treatments evaluated are currently selected routinely as first-line therapy for AECB. However, inflating all costs to 2003 U.S. dollars would be misleading in that it would imply that the studies are directly comparable. In addition, these studies represent standard treatment patterns in North America but are likely not generalizable worldwide. For example, Miravitlles and colleagues' analysis of costs and AECB reports that notably inexpensive costs for physician care in Spain lead to the need for country-specific studies. 14 Despite this, the current body of literature strongly suggests that drug acquisition price is not a key driver in costs and cost-effectiveness of AECB treatment. The relationship is likely not inverse; that is, higher priced medications are not necessarily more cost effective. Rather, these studies indicate that careful consideration must be given to clinical consequences, including the costly possibility of hospitalization, rather than solely to initial treatment costs. Further research is needed, however, to continue to evaluate newer treatments and treatment patterns in chronic obstructive pulmonary disease.

■■ Discussion and Conclusions
Based on the studies reviewed above, a number of conclusions regarding the costs associated with AECB can be made. First, it is clear that hospitalizations are responsible for a majority of AECB costs. For example, Niederman et al. 5 ) reported that more than 90% of AECB costs are due to hospitalizations. Halpern et al. 9 also indicated that hospitalization was the largest component of AECB costs, although the proportion of costs attributable to hospitalization (46% to 60%) did not reach that reported by Niederman et al. 5 Other European studies (e.g., van Barlingen et al. 15 ) have indicated that antibiotic acquisition costs account for a small propor-tion of total health care expenditure in patients with AECB.
Second, the choice of antibiotic can affect AECB costs. Costcomparison and cost-effectiveness studies have reported that differing antibiotics have differing impacts on treatment failure rates and on the length of time between AECB episodes. By decreasing failure rates and increasing time between AECB episodes, effective therapies decrease hospitalization rates and duration of hospitalization. For example, in the Destache et al. study, 7 while drug costs were lower for medications classified as first-line compared to third-line antibiotics, hospitalization rates were significantly higher among patients receiving firstline antibiotics, resulting in increased total costs for AECB.
Overall, the studies discussed in this review suggest that the least-expensive antibiotic is not necessarily the most effective or the overall least-expensive treatment. Even a slight increase in hospitalization rate or length of stay can more than offset costs resulting from more-expensive antibiotics. Further, as factors such as patient adherence to prescribed therapy and bacterial resistance patterns will influence treatment outcomes, characteristics of potential antibiotic therapies must be carefully evaluated. However, little is known about factors influencing a physician' s choice of antibiotic.
A small number of studies have evaluated physician choice of antibiotics. Trevisani et al. surveyed 118 general practitioners in the Italian National Health Service to evaluate physician habits and antibiotic preferences in the outpatient management of acute bronchitis and acute exacerbation of chronic bronchitis. 16 The findings suggest that quinolones and macrolides were the preferred antimicrobial agents for cases of AECB and that high-cost antibiotics were prescribed by 72% of general practitioners for AECB patients compared to 47.8% of general practitioners for acute bronchitis patients (P<0.001). Only a small number of physicians (9 of 118) reported taking into account cost prior to prescribing an antibiotic.
To a certain extent, the evaluation of cost-effectiveness of antibiotic treatment is a moving target. Long-term consequences of antibiotic use, particularly the development of resistance, are not addressed in these studies, yet they have a substantial potential impact on future costs and treatment patterns.
As managed care formulary decision makers require more information about cost-effectiveness, it is possible that physician-prescribing patterns will converge on the treatments that are most cost effective. However, other factors also influence physician treatment selections. Additional work is needed to evaluate factors influencing physician decision making for AECB treatments. Specifically, it will be important to understand how medication costs, overall treatment costs, and costeffectiveness of alternate therapies affect treatment decisions. This information can then be used to help guide formulary decision-management programs and develop disease-management programs. Appropriate and cost-effective AECB treatments will result in superior patient outcomes that provide the greatest value for the use of limited health care resources.